Structures of a) ofloxacin (R-form) ; b) levofloxacin.
For most drug substances single enantiomer is active. In such cases, the inactive enantiomer is considered an impurity, e. g. If the Dextro form is active then, in this case, levo form is considered an impurity.
An enantiomer can be named by the direction in which it rotates the plane of polarized light. An optical isomer can be named by the spatial configuration of its atoms. The clockwise rotation of the light traveling toward the viewer is labeled (+) or R (in Latin Rectus for right) also termed as d-isomer i.e. dextrorotatory enantiomer. Its mirror-image is labeled (−) or S (in Latin Sinister for left) also termed as l-isomer i.e. levorotatory enantiomer.
The R / S system is an important nomenclature system for representing enantiomers. This method labels each chiral center R or S according to a system by which its substituents are each assigned a priority, according to the Cahn–Ingold–Prelog priority rules (CIP), based on atomic number.
Enantiomeric Impurities
Chiral molecules are normally called enantiomers. Chiral separation plays a very important role in modern pharmaceutical analysis. Separation and identification of chiral impurities are very crucial. As per ICH guidelines, only the active enantiomer of the drug has to be marketed, so there is attention to the separation of the inactive enantiomer which acts as a chiral impurity. The impurities present in the enantiomers have similar chemical structures but different spatial orientations and pose various toxic adverse effects on bioavailability and efficacy. Hence it is essential to separate these impurities.
Presently there are more than 50% of the drug substances were chiral compounds. The enantiomers of chiral drugs can differ in their interactions with enzymes, proteins, receptors, and other chiral molecules, which results in differences in biological activity. The effect on biological activity can be further extended to variations in pharmacology, pharmacokinetics, metabolism, and toxicity. The body may metabolize each enantiomer by separate pathways to generate differing pharmacological activity. Therefore, one isomer may produce the desired therapeutic effect while another may be inactive or produce adverse effects.
Analytical Methods for Determination of Enantiomeric Impurities:
To ensure that chiral impurities are adequately controlled, suitable analytical methods are required. Several analytical techniques have been used for the determination of chiral impurities. Physicochemical methods that can be used to provide information about chiral drugs are listed below.
- High-Performance Liquid Chromatography (HPLC)
The Chiral HPLC method has been recognized to be one of the finest methods for chiral separation and quantification of enantiomers of chiral drugs. Chiral HPLC may be used to separate mixtures of enantiomers directly without forming diastereoisomeric derivatives. Separations can be achieved through the use of chiral stationary phases or chiral mobile phase in combination with achiral columns.
- Gas Chromatography
Stationary phases altered with chiral agents are available for the separation of enantiomers.
- Nuclear Magnetic Resonance (NMR)
NMR is a suitable instrument for the determination of enantiomeric composition. This is achieved by making the NMR signals for the protons of the enantiomers non-equivalent by the use of chiral lanthanide shift reagents, chiral solvating, or derivatizing agents.
- Capillary electrophoresis (CE)
Capillary electrophoresis is a fast method that uses cyclodextrins and substituted cyclodextrins as the most common chiral selectors.
- Polarimeter
This method can be used to distinguish between enantiomers because they rotate the plane of polarized light in opposite directions but in equal amounts.
- X-ray Diffractometer
X-Ray diffractometer in the solid state could be used for the estimation of the complete conformation of molecules and to differentiate conglomerates from racemic compounds.
- Melting Point
The melting points may be used in characteristic, specific enantiomers from the race-mate.
References:
- ICH, Q3A(R2) Impurities in New Drug Substances,
- ICH, Q3B(R2) Impurities in New Drug Products,
- ICH, Q2(R1) Validation of Analytical Procedures: Text and Methodology,
- Relationship between physical properties and crystal structures of chiral drug’’ Z.jane Li and David J.W.Grant,
- Encyclopedia of pharmaceutical technology,
- Tsukamoto M, Kagan HB (2002) Recent Advances in the Measurement of Enantiomeric Excesses,
- https://www.canada.ca/en/health-canada/services/drugs-health-products/drug-products/applications-submissions/guidance-documents, Guidance for Industry: Stereochemical Issues in Chiral Drug Development A.J.Romero and C.T.Rhodes,
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